J. Rick Turner, PhD

Biopharmaceutical drug development and therapeutic use are two components of integrated pharmaceutical medicine; drugs are developed to provide safe, therapeutic benefit to patients.

  Patient safety is of considerable current interest among multiple stakeholders in many countries, including the United States. The Food and Drug Administration (FDA), patients, and their prescribing physicians all have a vested interest in drug safety. The topic has attracted attention from Congress, the Supreme Court, the Institute of Medicine (IOM), pharmaceutical companies, patient advocacy groups, and the media.

Given that patient safety is of overriding importance, safety considerations are addressed throughout lifecycle drug development.

  Extensive safety evaluations occur throughout the range and diversity of preapproval clinical trials, postmarketing trials, and postmarketing surveillance. Similarly motivated investigations occur beforehand in two other phases of lifecycle development: drug discovery/drug design and nonclinical development programs. While attention in this article focuses on safety assessments in preapproval clinical development and therapeutic use, references are provided for readers who wish to learn more about nonclinical safety evaluations.

No drug can be guaranteed immune from side effects in all individuals, including those who are particularly susceptible for genetic and/or environmental reasons (e.g., slower-than-usual drug metabolism, race, food-drug interactions, drug-drug interactions). Accordingly, a drug's safety profile is assessed throughout drug development. The definition of "drug safety," however, is not as straightforward as one might initially think. One simple way to operationally define drug safety is to measure adverse events and adverse drug reactions (i.e., harm) and define safety as its inverse: the less the harm, the greater the safety.

  While useful conceptually, the FDA's Sentinel Initiative

  provides a more sophisticated definition:  

Although marketed medical products are required by federal law to be safe for their intended use, safety does not mean zero risk. A safe product is one that has acceptable risks, given the magnitude of benefit expected in a specific population and within the context of alternatives available. 

When considering a marketing application, regulators make a benefit-risk determination at the public health level. On the basis of all of the evidence in front of them at that point in time, and considering the target population in general, is it likely that the drug will have a favorable benefit-risk profile in the postmarketing setting? If an agency decides that the drug is indeed likely to have such a profile, it will be approved for prescribing in the agency's country of jurisdiction. At that point, prescribing physicians make a therapeutically-oriented benefit-risk decision in partnership with each patient who may benefit from the drug on a patient-by-patient basis. It is certainly the case that the benefit-risk profile may be favorable for one patient and not for another—the province of clinical decision making.

Regulators also consider the continuing benefit-risk profile of marketed drugs. Accumulating evidence of therapeutic effectiveness (or lack thereof) and adverse drug reactions can lead to meaningful reassessments of a drug's benefit-risk profile. A profile that was deemed favorable by a regulatory agency at marketing approval can become less favorable in their eyes, potentially leading to regulatory action. Additionally, as noted in the quote from the Sentinel Initiative, approval of other drugs with more attractive benefit-risk profiles can influence the favorability of an already marketed drug's benefit-risk balance. Benefit-risk decisions are therefore pervasive throughout integrated drug safety. 

As highlighted by the term lifecycle drug development, the transition from nonclinical to preapproval clinical development is best reflected as moving along a continuum, not as crossing a dichotomous chasm. As Amacher observed, translational biomarkers that have "in vitro, in vivo, and clinical transferability" are of particular value.

 Human pharmacology studies, typically conducted in healthy adults, are pharmacologically-oriented trials focusing on safety, understanding the drug's pharmacokinetic profile, estimating pharmacodynamic activity, and determining the best range of doses to employ in later trials. Examples include FIH trials, single- and multiple-ascending dose studies, drug-drug interaction studies, and maximum tolerated dose trials.  

Specific safety biomarkers are also examined. One cardiac safety biomarker of regulatory interest is drug-induced QT interval prolongation as seen on the surface electrocardiogram (ECG). QT interval prolongation is considered a surrogate (albeit an imperfect one) for the clinical endpoint of ultimate interest, a rare but potentially fatal polymorphic ventricular tachycardia called torsades de pointes. The 2005 ICH Guideline E14 and a related 2008 "Questions & Answers" document address the thorough QT/QTc study, a rigorous trial dedicated to the evaluation of torsadogenic liability.

  This trial adopts a three-component risk exclusion model, utilizing clinical, regulatory, and statistical sciences to identify unacceptable risk.

  An increase in QT/QTc prolongation below the limit of regulatory concern is demonstrated if the upper limits of two-sided, 90% confidence intervals (CIs), placed around the point estimates of the treatment effect (i.e., drug-induced QT prolongation) at all time points assessed lie below 10 milliseconds (msec).  

The literal operational definition of unacceptable risk is therefore an observation of QT/QTc prolongation of 10 msec or greater. However, regulatory concern is influenced by additional factors: the expected therapeutic benefit of the drug; the severity of the indication for which it is being developed; and the availability (or not) of other drugs for this indication and their benefit-risk profiles. Should regulatory concern arise, more extensive and intensive ECG monitoring than usual for a drug in that class may be required in subsequent therapeutic confirmatory clinical trials. 

Both therapeutic exploratory and therapeutic confirmatory studies are comparative in nature, looking for clinically and statistically significant evidence of efficacy. Importantly, the overall preapproval safety database continues to build during these trials. Additionally, as just discussed, additional specific safety data may be collected as appropriate. 

There is no doubt that information gained during preapproval clinical trials is an extremely important component of compiling a drug's safety profile and in providing the evidence that prescribing physicians use in conjunction with their patients when making pharmacotherapeutic decisions when a drug first becomes available; it is some considerable time until more comprehensive safety data are collected, collated, and disseminated following postmarketing collection. Nonetheless, data obtained during therapeutic use is of critical importance. As the IOM has noted, "The approval decision does not represent a singular moment of clarity about the risks and benefits associated with a drug—preapproval clinical trials do not obviate continuing formal evaluations after approval."

  Postmarketing clinical trials and postmarketing surveillance (passive and active) are components of such continuing formal evaluation. 

 Postmarketing trials can be relatively small compared with therapeutic confirmatory trials, perhaps investigating the drug's safety in alternate patient populations. They can also be much larger, such as those fulfilling postmarketing commitments when a safety signal has been noted by a regulatory agency during its review of a marketing application, but the overall benefit-risk judgment was sufficiently favorable to market the drug while the postmarketing trial is conducted.  

One example is the cardiovascular safety outcomes trial discussed in the 2008 FDA guidance addressing the development of new antidiabetic drugs for type 2 diabetes mellitus.

  Upon completion of such drugs' preapproval clinical development program, cardiovascular safety data from therapeutic exploratory and confirmatory trials must be used in a meta-analysis evaluating any degree of increased cardiovascular risk associated with the drug compared with the control treatment. A relative risk point estimate is calculated and a two-sided, 95% CI placed around it. Primary interest falls on the upper limit of the CI. Three scenarios are discussed:  

If the upper limit of the CI is equal to or greater than 1.3 but also less than 1.8, and the overall benefit-risk analysis presented at submission supports marketing approval, a subsequent step will generally be necessary. A postmarketing cardiovascular outcomes trial is required to definitively show that the upper limit of the CI is actually less than 1.3. 

If the upper limit is less than 1.3 and the overall benefit-risk analysis presented at submission supports marketing approval, "a postmarketing cardiovascular trial generally may not be necessary."

If the upper limit of this CI is equal to or greater than 1.8, the drug is deemed to have an unacceptable risk on the basis of the data collected to that point. In this case, a cardiovascular outcomes study "should be conducted that alone, or added to other trials, would be able to satisfy this upper [limit of the CI] before [New Drug Application/Biologic License Application] NDA/BLA submission."

  In this scenario, therefore, the cardiovascular outcomes study is actually a premarketing study.

The European Medicines Agency (EMA) has released similar guidance involving the same type of cardiovascular outcomes study.

  In that case, the study, if required, is to be conducted before requesting marketing approval.  

In addition to postapproval randomized (experimental) trials, postmarketing epidemiological (nonexperimental) studies can be informative. As Avorn commented, both are needed "to understand everything we should know about a drug."

 While perhaps initially surprising for those not familiar with drug development, it is (very) unlikely that (very) rare side effects will be observed in preapproval clinical trials, given the relatively small numbers of subjects for whom drug-related safety data are available. While preapproval clinical development programs are certainly complex, lengthy, and expensive, only around 3,000 (or less) participants receive the investigational drug. The "rule of threes"

  indicates that the sample size that would be needed in a clinical trial to be 95% confident that a single case of an adverse event of interest would be observed is roughly three times the reciprocal of the event's frequency in the general population. Accordingly, if 3,000 subjects are exposed to an investigational drug, we can be 95% certain of detecting any adverse events that occur in at least 1/1,000 individuals. Any events occurring less commonly, however, are unlikely to be detected. Many adverse events of interest occur much less frequently than 1/1000. For example, the incidence of drug-induced torsades de pointes is typically estimated to fall within a wide range of 1/10,000 to 1/1,000,000 recipients.

Postmarketing surveillance involves monitoring very large numbers of patients receiving a drug, with the goal of identifying and quantifying associated adverse drug reactions. The FDA's Sentinel Initiative discussed "an emerging science of safety, which combines a growing understanding of disease and its origins with new methods of safety signal detection," and addressed active surveillance as well as traditional "passive" surveillance.

Perceptions of safety signals and their consequences.

 It is a common misperception in the general public that the "identification" of a safety concern for a marketed drug reflects a failure on the part of the sponsor developing the drug and any regulatory agency that granted marketing approval. Identification of a serious risk (e.g., cardiac and cardiovascular concerns, aplastic anemia, and rhabdomyolysis) often leads to a "torrent of recriminations."

  Such recriminations are almost always directed at the biopharmaceutical sponsor, and the costs are considerable, ranging from loss of reputation to a decrease of billions of dollars in market capitalization. However, and perhaps increasingly so, they are also targeted at regulatory agencies.

The perception of a risk—whether or not the risk is real—attracts enormous media attention. As Turner et al. observed, "In the era of sensationalist, sound-bite coverage, clinical science sadly falls very low on the list of points to be covered in the allotted 30 seconds of television coverage (it can do somewhat better in print coverage)."

The Food and Drug Administration Amendments Act of 2007 (FDAAA),

  which was signed by President Bush on September 27, 2007 and became effective on October 1, 2007, is the third five-year renewal of the Prescription Drug User Fee Act of 1992 (PDUFA). Under PDUFA, sponsors pay a fee to the FDA every time an NDA or BLA is submitted. Of relevance to the topic of this article is that, while PDUFA and PDUFA II prohibited the use of fees for any postmarketing drug safety activities and PDUFA III allowed only around 5% of funds to be used in this manner (the focus was on getting effective drugs to market), this situation changed dramatically with the advent of the FDAAA (sometimes referred to as PDUFA IV). As reflected in Title IX, "Enhanced authorities regarding postmarket safety of drugs," drug safety is a key component of this act. This section provided the FDA with sweeping new safety authorities and significantly increased funding with which to pursue safety activities.  

Risk evaluation and mitigation strategies. 

Section 901, Subtitle A, Title IX, entitled "Postmarket Studies and Surveillance," introduced the risk evaluation and mitigation strategy (REMS). Prior to approving a drug for marketing, the FDA can now require a sponsor to provide a REMS that addresses how risk will be mitigated (hence safety optimized) once the drug is marketed. Additionally, if the FDA becomes aware of "new safety information" concerning a drug that is already marketed, new safety information being defined as information tied to a (perceived) serious risk associated with the drug, the agency can require a REMS to be submitted at that stage in the drug's lifecycle. 

Table 1 lists the components of a REMS. The timetable for submission of assessments will always be required, while others are required on a case-by-case basis. Details of the fifth component listed in Table 1, Elements to Assure Safe Use, are provided in Table 2.  

One example of the use of a REMS is provided by the FDA's requirement in September 2010 for the submission of a postmarketing REMS for rosiglitazone following a July 2010 joint meeting of its Endocrinologic and Metabolic Drugs Advisory Committee and its Drug Safety and Risk Management Advisory Committee.

Provision of complete risk information to each patient, and documentation in his/her medical record that this information has been received and understood.

Documentation from healthcare providers that each patient taking rosiglitazone falls into one of two groups: patients currently taking rosiglitazone and other individuals who are not able to achieve glycemic control on other medications, and who decide in consultation with their healthcare professional not to take pioglitazone (the other thiazolidinedione on the market) for medical reasons.

Documentation from healthcare providers that the risk information has been shared with each patient.

Physician, patient, and pharmacist enrollment. 

While this restricted access will likely reduce the number of individuals who will take rosiglitazone, the drug will stay on the US market and hence be available to patients for whom alternative treatment options are considered by them and their physicians to be less suitable.  

It is noteworthy that, based on the same data and announced on the same day as the FDA's decision, the EMA's Committee for Medicinal Products for Human Use voted to remove the drug from the European markets: the European Commission will make the final decision that will be legally binding for the 27 member countries in the European Union. This difference in regulatory action, however, is not the result of widely-diverging assessments of the available data.

  Rather, it reflects that the FDA has a useful tool, the REMS, at its disposal that can be used to facilitate the continued availability and use of rosiglitazone by a select group of patients for whom its benefit-risk balance is favorable: the EMA has no equivalent tool. 

Drug safety is assessed in all phases of lifecycle drug development. This article has focused on clinical trials and postmarketing surveillance, and illustrated various individual components that come together in the field of integrated drug safety. These include safety assessments in preapproval human pharmacology, therapeutic exploratory and confirmatory clinical trials, specialized safety studies, postmarketing clinical trials and postmarketing surveillance, and epidemiological studies. Benefit-risk estimations are also central components of safety assessment, regulatory decisions, and therapeutic decisions. As Turner and Durham observed, "Many professionals bring diverse sets of skills to the domain of drug safety. The more integrated the efforts of everyone concerned, the better all patients will be served."

PhD, Senior Scientific Director, Cardiac Safety Services, Quintiles, e-mail: 

 1. J. R. Turner, "Drug Safety, Medication Safety, Patient Safety: An Overview of Recent FDA Guidances and Initiatives," 

New Drug Development: An Introduction to Clinical Trials,

Histopathology of Preclinical Toxicity Studies,

 3rd Ed. (Academic Press/Elsevier, New York, 2007). 

Articles

Creating a drug's safety profile through the use of benefit-risk assessments during development.

Integrated Drug Safety

There is considerable interest in drug safety among multiple stakeholders in the United States, including the Food and Drug Administration (FDA), the National Institutes of Health, the Institute of Medicine (IOM), biopharmaceutical companies, Congress, individual congressional committees, the Supreme Court, patient advocacy groups, the media, and perhaps most importantly, prescribing physicians and their patients.

  Given that no drug is immune from the possibility of causing adverse events in certain genetically and/or environmentally susceptible individuals, an operational definition of "safety" is needed. A useful general definition is found in the FDA's Sentinel Initiative:

Using medical products brings benefits and risks. Although marketed medical products are required by federal law to be safe for their intended use, safety does not mean zero risk. A safe product is one that has acceptable risks, given the magnitude of the benefit expected in a specific population and within the context of alternatives available.  

This definition, which encapsulates the concept of benefit-risk assessment, "one of the important facets of the science of safety,"

 applies very well in the science of cardiac safety. An investigational drug must be found by an agency to have a favorable benefit-risk balance to receive marketing approval. It is the responsibility of sponsors to provide regulatory agencies with the most accurate and thorough safety (and efficacy) data possible at the time of requesting marketing approval, and it is also in their own best interests, as discussed later.  

Between the late 1980s and the early 2000s, a series of high-profile drug marketing withdrawals for cardiac reasons focused regulatory attention on this issue. Of particular relevance is one form of polymorphic ventricular tachycardia, torsades de pointes, that is very rare but can be fatal.

  Several hundred deaths from widely-prescribed drugs for relatively benign conditions (including terfenadine, an antihistamine, for allergies) indicated that the benefit-risk balance for these drugs was unacceptable.

Torsades de pointes is associated with QT interval prolongation as seen on the surface electrocardiogram (ECG). Figure 1 provides a stylistic representation of the QT interval and the phenomenon of QT interval prolongation.  

Figure 1: Stylistic representation of the QT interval and QT interval prolongation.			

Each segment of the ECG can be assigned a length in the time domain. The QT interval represents the total time of cardiac muscle cell depolarization (contraction) and repolarization (returning to the relaxed state such that contraction can occur again). It is defined as the length in the time domain from the onset of the Q-wave to the off-set of the T-wave, measured in milliseconds (msec). Precise categorization of the "normal QT interval" for any individual is impractical since it changes with every heart beat. However, consideration of the typical ranges observed in groups of individuals following a period of supine rest provides some perspective. Since the QT interval is impacted by heart rate, tending to be shorter as heart rate increases, it is typically "corrected for heart rate" by one or more of several mathematical formulas, resulting in QTc data. In this context, the normal distribution of QTc intervals for healthy adult males suggests a range from around 350-460 msec. For healthy adult females, the distribution is similar but falls around a somewhat higher mean, suggesting a range from around 360-470 msec.

Given the association between torsades de pointes and QT prolongation, regulatory agencies in Europe, Canada, Japan, and the United States now require a dedicated trial to assess the impact (if any) of an investigational drug on the QT interval. This trial is called a Thorough QT/QTc (TQT) Study, and is described in the 2005 ICH Guideline E14.

   While assessment of the QT risk of new drugs had certainly been addressed beforehand,

  the adoption of ICH E14 by regulatory agencies formalized clinical cardiac safety assessment.  

The TQT is a rigorously controlled clinical trial. This rigor includes using identical monitoring equipment for each subject to collect multiple digital ECGs, transmitting them to a core ECG laboratory (core lab), and having all QT/QTc measurements for a given study performed at a core ECG lab in a blinded manner by a relatively small number of highly experienced technicians or cardiologists. In addition, the Phase I units conducting these trials must ensure that the subjects in each cohort are treated identically to ensure consistency in conduct. These centralized, standardized processes greatly enhance the quality and integrity of the data.

  The logic here is similar to that behind the use of a single central laboratory (central lab) to analyze biological samples collected at multiple investigational sites. Standardization ensures consistency of many factors that can influence readings, including instrumentation, reference ranges, personnel, environment, and reagents.

  More detailed discussion of the TQT study and torsadogenic liability can be found in many sources.

Moving beyond QT/QTc interval prolongation 

While ICH E14 has made QT/QTc prolongation a high-profile cardiac safety biomarker, it is widely acknowledged to be imperfect, and, by itself, it is not now sufficient for regulatory evaluation of a drug's cardiac safety when requesting marketing approval. Other assessment methodologies include concentration-QT/QTc modeling,

  assessment of additional ECG intervals such as the PR interval and QRS duration, as well as heart rate, and various characteristics of ECG morphology.

  Importantly, as for QT/QTc interval prolongation, all these additional ECG data points benefit considerably from a centralized, standardized analysis strategy.

Current lack of centralization for Phase III data

In stark contrast to the approach mandated for the TQT study, the majority of ECG data from other trials worldwide is still collected and analyzed in a decentralized manner. This fragmented, non-standardized approach to collecting cardiac safety data is characterized by the use of different ECG machines (and/or different vintages of the same machine) at different sites, and the common use of paper print-outs of the ECGs.

  For historical reasons, many machines that calculate QTc values employ the Bazett correction formula, which is arguably the most inaccurate.

 Heterogeneity of equipment and software from different manufacturers introduces inconsistency. Kligfield et al. confirmed this long-held suspicion and concluded that systematic differences in QT measurements between manufacturers are significant and must be considered when used as markers of arrhythmogenic risk.

  Individual printers can introduce errors by distorting the paper as ECGs are being printed. Different physicians at different sites then read these print-outs. While undoubtedly highly qualified in their own medical specialty, not all of these physicians will be highly trained and experienced in cardiac electrophysiology, and in the measurement and interpretation of ECG intervals and waveforms (see also Viskin et al.

Further confounding late stage developmental studies is the extreme difficulty in overcoming the logistical issues involved. These trials typically engage large numbers of subjects over several years, and are therefore conducted in multiple outpatient settings. ECG acquisition characteristically consists of single tracings unaligned to pharmacokinetic peaks. The high degree of QT interval variability in even normal subjects challenges the significance of solo measurements as opposed to mean QT values. Likewise, strategic sampling at peak drug concentrations would increase reliability.   

As disclosed at the end of this article, the authors work for commercial vendors of centralized, standardized, cardiac safety services, and these central labs stand to gain financially should wider adoption of the standardized system occur. That acknowledged, in the authors' collective opinion, employment of the centralized system for ECG data from Phase III trials is in the best interest of patients (the primary consideration) and also in the best interests of sponsors and regulators. No one questions that centralization of biological samples (their analysis at central labs) should be used in Phase III trials. Patients benefit every time optimum quality data are used in drug research, and, in the present context, they are best served when a sponsor utilizes a core lab and presents regulators with ECG data that permit the best possible assessment of the degree (if any) of cardiac risk. If a cardiac risk is identified and the drug's likely benefit is deemed to sufficiently outweigh the cardiac risk, the drug can still be approved. In this case, biopharmaceutical sponsors and regulators will employ risk minimization strategies. These approaches can allow the (possibly very large) majority of potential patients to reap the benefits of the newly approved drug while providing maximum protection to patients for whom a different treatment modality is preferable. 

A major reason that many sponsors do not currently employ centralized approaches in Phase III trials is the misperception that it is considerably more expensive to do so. Therefore, in the absence of a regulatory mandate, they choose to use the decentralized approach. As Furlong

  observed, "It remains a challenge for core labs to fully demonstrate to sponsors the added value brought about by centralization as well as the cost-savings realized through the complete study management process." Some members of our industry have already written on this topic

   but all of us who work at core labs need to do more in this regard.  

With regard to agency guidance, regulators have not yet addressed centralization of cardiac safety in later phase trials. It appears that cardiac safety core laboratories and the biopharmaceutical sponsors they work with will need to continue to explore the benefits that centralization has to offer in order to drive this process forward. One obstacle to this is the extreme focus on QT as a surrogate for cardiac safety. In Phase III trials, for drugs that have no QT changes in a TQT study, the focus should be on morphology rather than QT.  

To these authors, it would seem prudent to use a strategy that is acknowledged to provide higher quality data for a (somewhat) more heterogeneous subject sample as typically employed in a Phase III trial to assess cardiac parameters as carefully as possible. From a workload perspective, reviewing data collected in a centralized manner rather than a decentralized one would not require extra work. To the contrary, higher quality data would potentially decrease the time needed. The downside, therefore, is not readily apparent. In contrast, the upside is clear: Higher quality data would provide greater assurance that potential risks had been looked for as thoroughly as possible in the preapproval data, the only data available at that time (subsequent postmarketing data are always to be considered once available). It is quite conceivable that a risk that would not have been identified with the data acquired from a decentralized approach would indeed be identified in data acquired in the manner advocated in this article, and hence regulators would have the opportunity to protect the public health in the manner they deemed most appropriate in the context of the magnitude of the risk and the magnitude of the drug's likely benefits.  

Additional benefits to the centralized approach

The perception of a cardiac and/or cardiovascular risk being associated with a marketed drug—whether or not the risk is real—attracts enormous mass media attention. In the era of sensationalist, sound-bite coverage, clinical science sadly falls very low on the list of points to be covered in the allotted 30 seconds of television coverage (it can do somewhat better in print coverage). When a cardiac or cardiovascular safety concern is "identified" for a marketed drug, there is frequently a "torrent of recriminations."

 Such recriminations are almost always directed at the biopharmaceutical sponsor, and the costs are considerable, ranging from loss of reputation to a decrease of billions of dollars in market capitalization. However, and perhaps increasingly so, they are targeted at regulatory agencies too. In addition to being in the best interests of patients, the paramount concern, doing everything possible to identify any degree of cardiac risk in preapproval trials is in the best interests of sponsors and regulators. 

The centralized, standardized data collection process employed for TQT studies greatly enhances the quality and integrity of the data acquired and analyzed. Currently, in contrast to this approach, the majority of ECG data from other trials worldwide is still collected and analyzed in a fragmented, non-standardized manner. Many sponsors do not currently employ centralized approaches in Phase III trials because of the pervasive misperception that it is considerably more expensive to do so. Those of us who work at ECG core labs need to do more to increase sponsors' awareness of the added value brought about by adoption of a centralized approach as well as the cost-savings realized through the complete study management process being placed with a core lab. In addition, and moving beyond the vendor, biopharmaceutical sponsors then need to take joint responsibility with us in furthering the science of cardiac safety.  

The authors work for commercial vendors of centralized cardiac safety services. 

,* PhD, is Senior Scientific Director, Cardiac Safety Services, at Quintiles, Durham, NC, e-mail: 

, MD, FACC, is Chief Medical Officer at Cardiocore, Bethesda, MD. 

, PhD, is Chief Scientific Officer at Biomedical Systems, St. Louis, MO. 

, MD, FACC, is  Executive Vice President and Chief Medical Officer at ERT, Philadelphia, PA.

*To whom all correspondence should be addressed.

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The Sentinel Initiative: A National Strategy for Monitoring Medical Product Safety

3.  F. Dessertenne, "La Tachycardie Ventriculaire A Deux Foyers Opposes Variables," 

Integrated Cardiac Safety: Assessment Methodologies for Noncardiac Drugs in Discovery, Development, and Postmarketing Surveillance

. (John Wiley & Sons, Hoboken, NJ, 2009). 

5.  T. J. Bunch and M. J. Ackerman, "Cardiac Channelopathies," in 

, 3rd Edition, J. G. Murphy, and M. A. Lloyd, eds. (Mayo Clinical Scientific Press/Informa Healthcare USA, Boca Raton, FL), pp. 335-344. 

The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-antiarrhythmic Drugs

7.  ICH Guideline E14 Implementation Working Group, 

The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-antiarrhythmic Drugs: Questions & Answers

8.  "CPMP: Points to Consider on the Assessment of the Potential for QT Interval Prolongation by Non-Cardiovascular Medicinal Products," (CPMP/SWP/986/96.). 

9.  J. Morganroth, F. V. Brozovich, J.T. McDonald, and R.A. Jacobs, "Variability of the QT Measurement In Healthy Men: With Implications for Selection of an Abnormal QT Value to Predict Drug Toxicity and Proarrhythmia," 

10. S.E. Steare and J. Morganroth, "A Rational Approach to the Planning and Analysis of Electrocardiogram Safety Data in Clinical Trials," 

International Journal of Pharmaceutical Medicine

11. A. Furlong, "Cardiac Safety: Cost to Trials," 

New Drug Development: An Introduction to Clinical Trials

13. W.S. Redfern, L. Carlsson, A.S. Davis, et al., "Relationships Between Preclinical Cardiac Electrophysiology, Clinical QT Interval Prolongation and Torsade De Pointes For A Broad Range Of Drugs: Evidence for a Provisional Safety Margin in Drug Development," 

14. G.J. Noel, D. B. Goodman, S. Chien, et al., "Measuring the Effects of Supratherapeutic Doses of Levofloxacin on Healthy Volunteers Using Four Methods of QT Correction and Periodic and Continuous ECG Recordings," 

Cardiac Safety of Noncardiac Drugs: Practical Guidelines for Clinical Research and Drug Development

16. C. Strnadova, "The Assessment of QT/QTc Interval Prolongation in Clinical Trials: A Regulatory Perspective," 

17. P. Kligfield, B. Tyl, M. Marek, and P. Maison-Blanche, "Magnitude, Mechanism, and Reproducibility of QT Interval Differences Between Superimposed Global and Individual Lead ECG Complexes,"  

18. C.M. Beasley, Jr, A. Dmitrienko, and M.I. Mitchell, "Design and Analysis Considerations for Thorough QT Studies Employing Conventional (10s, 12-Lead) ECG Recordings," 

Centralized approach for Phase III studies enhances the quality and integrity of collected data.

J. Rick Turner, PhD

Articles

Integrated Drug Safety

The Science of Cardiac Safety